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MARCH / APRIL 2010
Supplement to VOL 21 NO 2
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CardioVascular Journal of Africa (official journal for PASCAR)
International Symposium
Integrated Approach to
Disease Management:
Endocrinology, Metabolic
Disorders and Cardiac
Consequences
Cape Town
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References: 1. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood glucose control with metformin on complications in overweight patients with Type 2 Diabetes (UKPDS 34). Lancet 1998;352:854-65. 2. Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycaemia in
Type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologica 2006;49(8):1711-1721. 3. Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up
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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 2, March/April 2010
1
Report on the first international symposium, Integrated Approach
to Disease Management: Endocrinology, Metabolic Disorders and
Cardiac Consequences, Middle East, Russia and Africa
Cape Town, 6–7 March 2010
Diabetes and thyroid disease interactions and their cardiac consequences
The need for an integrated approach to diabetes and thyroid disease management resulted in the organisation of a special symposium
between the developing regions of the Middle East and Africa, sponsored by Merck Serono.
Experts in diabetes and thyroid dysfunction addressed the known and emerging cardiometabolic consequences of these conditions;
applying new knowledge to the particular circumstances of developing regions, represented by delegates from Saudi Arabia, Iran,
Lebanon, Egypt, Morocco, Russia and South Africa.
The thyroid and type 2 diabetes
In the first keynote lecture, Prof Klaus
Badenhoop, Jahan Wolfgang Goethe
University, Frankfurt noted that fluctuations in thyroid hormone levels, even in
patients treated for their thyroid disorder, adversely affect glucose homeostasis, increasing the risk of atherosclerotic
events. ‘As insulin and thyroid hormones
are intimately involved in metabolism
at a cellular level, it is inevitable that
any excess or deficit of either endocrine
hormone will impact on the cardiometabolic environment.
In addition, another endocrine organ,
brown adipose tissue, which stimulates
thermogenesis and regulates energy
homeostasis, is activated by thyroid
hormones. Brown adipose tissue forms a
further physiological link between diabetes, thyroid disorders and weight gain,
leading to the metabolic syndrome’, he
noted.1
Brown adipose tissue is now also being
targeted as a new therapeutic area for the
treatment of obesity, as it and subcutane-
ous white adipose tissue (but not visceral hypothyroidism, perhaps reflecting a
white adipose tissue) have the potenhigher level than anticipated by many
tial to benefit metabolism by improv- physicians.
ing glucose homeostasis and increasing
‘The cardiovascular consequences of
energy consumption.
the subclinical hypothyroid state has also
The cardiovascular effects of thyroid been substantiated in a recent meta-analhormone are exerted on heart rate, ysis3 and with the convincing 20-year
systemic vascular resistance and cardiac follow up of the Whickham study4 which,
output (Fig. 1). The cardiovascular conse- when evaluating the cardiovascular
quences of hypothyroidism are also well consequences in untreated patients with
known and are summarised in Fig. 2 and subclinical hypothyroidism (SCH) and
without ischaemic heart disease (IHD) at
Table 1.
With regard to the dual occurrence of study entry, found a significantly higher
thyroid disorders and type 2 diabetes, an incidence of IHD and IHD mortality in
interesting study
from Taiwan2 has
TABLE 1. CHANGES IN CARDIOVASCULAR
found that subcliniFUNCTION IN HYPOTHYROIDISM
cal hypothyroidism
Normal range Hypothyroidism
occurs
quite
Systemic vascular resistance
1500–1700
2100–2700
commonly in type
Heart rate (beats/min)
72–84
60–80
2 diabetes; 7.2%
Ejection
fraction
(%)
50–60
≤ 60
of diabetes patients
Cardiac
output
(l/min)
4.0–6.0
<
4.5
in this cohort
Isovolumic
relaxation
time
(msec)
60–80
>
80
of 600 patients
Blood
volume
(%
of
normal
value)
100
84.5
had subclinical
Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J
hypothyroidism
Med 2001; 344: 501–509
and 3% overt
Genomic/non-genomic actions
Heart
Rate
Systolic
function
Systemic
vascular
resistance
Diastolic
function
Performance
Biondi B and Klein I., The Thyroid and Cardiovascular Risk, Thieme 2004.
Fig. 1. Effects of thyroid hormone on the cardiovascular
system.
•• Haemodynamic changes
–– Increase in vascular resistance
•• Decreased vasodilator action of T3 and NO
–– Impaired ventricular performance
•• Changes in the expression of myocyte-specific
regulatory proteins
•• Increased cardiovascular risk
–– Increased risk for functional cardiovascular abnormalities
–– Inreased risk for atherosclerosis
Klein I.L. The cardiovascular system in hypothyroidism. In: Braverman LE, Utiger RD, eds.
The Thyroid. 9 ed. Philadelphia: Lippincott Williams & Wilkins. 2005: 774–780. Biondi B.,
Klein I. Hypothyroidism as a risk factor for cardiovascular disease. Endocrine 2004; 24: 1–13
Fig. 2. Cardiovascular effects of hypothyroidism.
2
CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 2, March/April 2010
the SCH group. These findings lost their
significance when patients who had been
treated with levothyroxine were included
in the analysis.
The Taiwanese study,2 which was
undertaken to investigate the relationship
between subclinical hypothyroidism and
the prevalence of retinopathy, nephropathy and cardiovascular disease, showed
that the higher cardiovascular events in
these SCH patients are likely to be related
to higher rates of nephropathy.
‘It is clear from these studies that
we need to identify and treat subclinical hypothyroidism in type 2 diabetes
if we wish to reduce ischaemic heart
disease morbidity and mortality’, Prof
Badenhoop noted.
A recent study on the relationship
between mild thyroid dysfunction in
cardiac patients5 has also highlighted the
fact that survival rates were lower in
patients with subclinical hypothyroidism
and in those with low T3 levels, but were
not altered in subclinical hyperthyroidism
(Fig. 3).
Prof Badenhoop concluded that at least
20% of diabetic patients will have some
manifestations of thyroid dysfunction and
this needs to be addressed in diabetes
control strategies. ‘Treatment goals need
to be individually tailored to patient needs
and profile in order to achieve physiologically adapted metabolism for lipids,
glucose, heart and vascular systems’, he
stressed.
Pathophysiology of type 2 diabetes
‘There is a complex sequence of physio-
4.5
p < 0.001
4
3.5 p = 0.02 p = 0.02
p < 0.002
The role of guidelines in optimising type 2 diabetes management
The need to monitor and up-titrate interventions in type 2 diabetes management is
paramount and should be done at as rapid
a pace as titration of medication allows.
Also, early metformin usage needs to be
expanded in many regions of the world.
These views were expressed by Prof Sami
Azar of the American University of Beirut
Medical Centre, Lebanon in his presentation on different individual regions.
‘Regions of the Middle East and North
Africa (Tunisia, Morocco and Egypt) are
facing a projected 81% increase in diabetes prevalence over the next 25 years,
based on the 2003 International Diabetes
Federation figures’, Prof Azar pointed
out. ‘This means that the number of
people with diabetes in the Middle East is
set to more than double due to population
growth, ageing and urbanisation trends.’
Of interest is that research on the use
of metformin as initial therapy has shown
a-cell
dysfunction
2.5
n.s
1.5
1
Liver
0.5
Cardiac
Death
Euthyroid
Overall
Death
IHD
SCHypo
Inadequate
Insulin
PRE/POST MEAL
HYPERGLYCAEMIA
n.s
n.s
2
b-cell
dysfunction
Increased
Glucagon
p < 0.001
3
0
including a deficiency of GLP-1 and
resistance to the action of gastric inhibitory peptide (GIP).7 The GLP-1 deficiency
can already be seen in individuals with
impaired glucose tolerance (IGT) and it
worsens progressively with type 2 diabetes.
Highlighting the importance of the role
of impaired insulin secretion, decreased
muscle glucose uptake, increased hepatic
glucose production and decreased hepatic
glucose uptake in type 2 diabetes can
aid the clinician in his management of
patients over time (Fig. 4).
Pancreas
5
Hazard Ration (95% CI)
logical abnormalities that interact to
produce the syndrome of type 2 diabetes.
Understanding the pathophysiology and
aligning our management of the condition to these circumstances presents an
opportunity to refresh current guidelines.’
This view was expressed by Prof Joshi,
director of the Diabetes Care Centre,
Pretoria and emeritus professor of medicine, MEDUNSA, South Africa.
‘Both pancreatic β- and α-cell dysfunction resulting from insulin resistance lies
at the centre of the progression of type
2 diabetes pathology (Fig. 4), affecting
the functioning of target organs – liver,
muscle and adipose tissues, with resultant
glucotoxicity and lipotoxicity.6
Insulin secretory defects in type 2
diabetes are characterised by abnormal
patterns of basal pulsatile insulin secretion, decreased insulin capacity, decreased
β-cell sensitivity to glucose, loss of firstphase insulin secretion in response to
glucose and reduced second-phase insulin response, increased release of proinsulin and split products, morphological
pancreatic changes with reduced β-cell
mass, and amyloid deposits and defective
glucose potentiation in response to nonglucose insulin secretagogues.
Βeta-cell failure is also a feature of
advancing age and genetic predisposition.
‘Several genes have been shown to be
associated with β-cell dysfunction in type
2 diabetes, affecting transcription factors
and responsiveness to GLP-1’, Prof Joshi
noted.
In type 2 diabetes, there are also abnormalities related to the incretin effect,
AFRICA
Non-IHD
Increased
glucose
production
Reduced
glucose
uptake
Decreased
GLP-1/GIP
Adipose Tissue
& Muscle
SCHyper
Lervasi G., et al. Arch Intern Med 2007; 167 (14)
Fig. 3. Association between increased mortality and
thyroid dysfunction in cardiac patients.
GIT
INSULIN RESISTANCE
Adapted from De Fronzo RA. Diabetes 1988; 37: 667–687
Fig. 4. Pathophysiological defects.
FFA
AFRICA
lower metformin initiation in the Middle
East than in the United Kingdom (Fig.
5). Seeking to address cost-effective type
2 diabetes management, an expert panel
of physicians in the Middle East developed an easy-to-understand and easily
implementable algorithm for primary care
level8 (Fig. 6).
Prof Azar noted that in poorly resourced
communities, the addition of sulphonylureas and other oral anti-diabetic agents is
the step most often chosen. ‘The need to
reinforce lifestyle message and maintain
metformin therapy should be stressed at
all visits, at three- and six-monthly intervals. The usage of metformin is advocated for all severities of hyperglycaemia, at all body weights and at all ages
unless contra-indicated by renal disease
or gastrointestinal (GI) intolerance. In the
latter instance, switching to a once-daily
slower-release formulation may improve
GI intolerance’, Prof Azar said.
‘The recent recommendation from the
American Diabetes Association to solely
use HbA1c as a diagnostic measure of
type 2 diabetes is problematic in Africa
and many developing regions, as many
patients are iron deficient and anaemic,
and standarised HbA1c assays are not
always available’, Prof Azar concluded.
New therapies in type 2 diabetes
management
Middle-East
of patients, namely: rising HbA1c levels tin, are oral agents that target post-pranover time, 4% β-cell loss per year, serious dial glycaemia and do not cause hypoglyand fatal macrovascular consequences caemia. ‘They are weight neutral, unlike
largely unaltered, and obesity. ‘In fact, the GLP-1 analogues which cause weight
the proportion of patients reaching HbA1c loss’, Dr Distiller pointed out. ‘Data on
targets may well be declining and so the the long-term use of these agents are also
time for serious reflection is now’, he lacking and the continued safety profile
noted.
needs to be established, Dr Distiller
Concentrating on new therapies but warned. ‘Other agents such as pramlinexcluding in-depth discussions on insu- tide, an amylin analogue and dapagliflozlins, PPAR agonists and bariatric therapy, in, an inhibitor of renal glucose uptake are
Dr Distiller noted that new forms of old as yet untested agents, which, although
drugs, such as sustained-release prepara- offering physiological rationales for use,
tions and combinations of drugs offer need further efficacy and safety testing’,
the advantage of simplifying medica- he noted.
tion regimens and improving compliance.
‘Perhaps we need to return to lifestyle
‘We need to support patient compliance change as a highly effective way of treatbecause of studies showing how increased ing diabetes and truly adopt the motto
dosage frequency to a mere twice-a- ”lifestyle change is the cornerstone of
day regimen of sulphonylureas reduces type 2 diabetes” in order to achieve better
compliance by a very significant 33%’9, results’, Dr Distiller concluded.
Dr Distiller added.
The new agents that focus on targeting
Megatrials on metformin:
the defective incretin hormone function
in type 2 diabetes are GLP-1 analogues importance for Africa
and DPP-IV inhibitors, which are now ‘The numbers of people in Africa who will
becoming available in developing coun- develop type 2 diabetes are set to increase
tries. ‘The exciting aspect of the GLP-1 dramatically as longevity improves in
analogues, exenatide and liraglutide, is the these countries, accompanied by rapid
prolongation of β-cell function, increas- urbanisation. Egypt is likely to have 8.6
ing proliferation and inhibiting apoptosis million diabetics by 2030, earning it an
of β-cells (Fig. 7). However, to maximise unenviable place in the list of top 10
their benefits to our patients, these agents countries contributing to the patient load
should be used early in the diabetes treat- worldwide.’
Presenting this view, Prof Fahmy
ment algorithms. This early use will not
take place unless
the drugs become
cheaper and safety
Begin with lifestyle/metformina,b
outcome data are
more secure after
If HbA1C remains ≥ 7.0%
long-term therapy’,
Dr Distiller noted.
Add
Add SU
The
DPP-4
basal
(or consider TZD,
inhibitors, sitaglipinsulin
DPP-4 inhibitor of AGIC)
tin and vildaglipUK
Other (3%)
SU
(53%)
Metformin
(37%)
Other
(21%)
Metformin
(79%)
Fig. 5. Current use of metformin in the region.
If HbA1C remains ≥ 7.0%
Intensive insulin ± metformin
or other oral agentsd
Maintain metformin + lifestyle
intervention throughout
‘Despite more complex treatment of type
2 diabetes, which include new and more
expensive drugs, we are not doing any
better in achieving better glucose control
for our patients.’ Expressing this view in
his comprehensive update on new therapies in the management of type 2 diabetes, Dr Larry Distiller, South Africa’s
champion of total care systems for diabetic patients, stressed the still unmet needs
TZD
(17%)
3
CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 2, March/April 2010
Fig. 6. Proposed algorithm for the management of type
2 diabetes in the Middle East. aInsulin may be required
initially to stabilise patients presenting with severe hyperglycaemia. bA short trial of lifestyle intervention (e.g. one
month) may be given before starting metformin (lifestyle
intervention and metformin may be co-prescribed where
additional clinic visits are problematic for the patient).
c
When appropriate for an individual patient. dAvoid combination of insulin with a thiazolidinediones (TZD) because
of increased risk of oedema. Referral to a specialist will
be appropriate for some patients.
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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 2, March/April 2010
Amara, emeritus professor, Alexandria
University and president of the Egyptian
Association of Endocrinology, Diabetes
and Atherosclerosis, pointed out that
the Diabetes Prevention Program (DPP)
conducted in 2001 included a very large
sample (45%) of patients with impaired
glucose tolerance, representing ethnic
minorities (African and Asian groups).
‘This, together with the Indian DPP
cohort of patients, led to the 2006
International Diabetes Federation consensus on type 2 diabetes management for
both developed and developing countries,
which focused on the value of lifestyle
and metformin therapy. Metformin (850
mg twice daily) reduced the relative risk
of progressing to type 2 diabetes by
31%, while intensive lifestyle counselling
reduced the risk by 58%.
Recently, the 10-year follow up of the
majority (88%) of the patients initially
recruited into the DPP was completed. In
this evaluation, the reduction of diabetes
incidence was maintained but at a lower
level; 18% in the metformin group and
34% in the lifestyle group.
Contrasting these results in IGT
patients to the 10-year follow up of diag-
nosed type 2 diabetes patients recruited in
the UKPDS study, Prof Amara noted that
here also the effect of earlier metformin therapy was sustained. ‘The legacy
effect of metformin in type 2 diabetes,
even when initiated early, is an excellent
outcome for developing countries with
limited health budgets, as metformin therapy is cheap, effective and has minimal
side effects, Prof Amara concluded.
Metformin’s role in reducing
cardiovascular and other
conditions in IGT and nondiabetic patients
Metformin’s action as an insulin sensitiser
is key to its beneficial effects in reducing
cardiovascular events along the continuum of dysglycaemia. ‘The evidence of
metformin’s value in non-diabetics is
limited, but there is some promising, if
perhaps speculative evidence that it can be
cardioprotective in non-diabetic high-risk
patients’, pointed out Dr Ian Campbell, St
Andrews, United Kingdom.
Referring to an older, direct study in
non-diabetics with dyslipidaemia, mainly
hypertriglyceridaemia and heart disease,
metformin therapy
TABLE 2. UKPDS: OUTCOMES OF
reduced angina
INTENSIVE GLYCAEMIC THERAPY
and myocardial
Metformin
Sulphonylurea/
ischaemia in these
intensive
insulin intensive
patients by 70%.10
Change
Change
A more recent
in risk* p-value in risk* p-value
study of nonDiabetes-related deaths
↓ 42% 0.017
↓ 20%
0.19
diabetic patients
All-cause mortality
↓ 36% 0.011
↓ 8%
0.49
with angina and
Any diabetes-related endpoint
↓ 32% 0.0023 ↓ 7%
0.46
without coronary
Myocardial infarction
↓ 39%
0.01
↓ 21%
0.11
artery
disease
Stroke
↓ 41%
0.13
↑ 14%
0.60
CV benefits substantially greater for metformin but all treatments were
equivalent in controlling hyperglycaemia
*Compared with conventional therapy (overweight group)
UK Prospective Diabetes study group. Lancet 1998; 352(9131): 854–865.
GLP-1 treated cells
Day 1
Day 3
Islets treated wtih
GLP-1 in culture
were able to maintain their integrity
for a longer period
of time
Day 5
(cardiac syndrome X) (Fig. 8) showed
improved angina symptoms and increased
forearm blood flow in those patients
receiving metformin.11
‘The mechanism of metformin vasodilation is perhaps the result of structural similarities between metformin and
arginine, the potent precursor of nitric
acid. Also metformin lowers CRP by 30
to 50%, which is indicative of a cardioprotective mechanism’, Dr Campbell
noted.
‘If one turns to the circumstantial
evidence, the UKPDS offers some
tantalising views. After all, insulin and
the sulphonylureas were equivalent to
metformin in terms of controlling hyperglycaemia; but metformin was the only
agent to show substantially greater cardiovascular benefits’ (Table 2). ‘This implies
the involvement of other pharmacological actions of metformin’, Dr Campbell
pointed out.
Polycystic ovarian syndrome (PCOS),
if regarded as a pre-type 2 diabetes condition with underlying insulin resistance,
when treated with metformin during
pregnancy, resulted in far fewer women
developing gestational diabetes. Again,
this indicates a cardioprotective role, as
women with gestational diabetes experience increased cardiovascular events in
later life, as evidenced from a Canadian
study of extended follow up.12
‘Metformin’s role as an adjuvant in
cancer therapy with some 55 ongoing
trials could result in a further research
lifespan of metformin beyond its current
52 years’, Dr Campbell said. ‘Its anticancer action in prostate, breast and bowel
12
10
% Patients
Control
AFRICA
*
8
6
4
2
0
Reinfarction Symptoms
of angina
*p = 0.003
Follow-up 3 years
T2DM 34%, IGT 52%, NGT 14%
Acute CV
events
Deaths
Controls (n = 123)
Metformin (n = 187)
Sgambato S., et al. Clin Ther 1980; 94: 77–85.
Fig. 7. GLP-1-preserved morphology of human islet cells
in vitro.
Fig. 8. Three-year outcomes for post-MI patients treated
with metformin.
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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 2, March/April 2010
cancer is likely to be due to activation of
LKB 1, an anti-tumour factor.’
Referring to the use of metformin
in chronic congestive heart failure, Dr
Campbell pointed out that if the patient
is stable and ambulatory, he would use
metformin at a left ventricular ejection
fraction above 30%, based on the study
results showing improved survival of
diabetic patients with heart failure.13
In conclusion, Dr Campbell noted
the excellent contributions from South
African experts over many years, including the outstanding work by Profs WPU
Jackson and EJ Coetzee on gestational
diabetes.
Focus on thyroid dysfunction
The second day of the symposium focused
on thyroid dysfunction.
Current aspects of thyroid
hormone actions – a research
view
Prof Theo Visser of Rotterdam Erasmus
University in the Netherlands gave an
overview of the complex mechanisms
involved in thyroid hormone transport
into and out of cells. ‘For transport to take
place, specific transporters are required
to mediate the process. It does not simply
take place by passive diffusion, as was
once thought. There are two types: organic anion transporters and amino acid/
monocarboxylate transporters.’
He spotlighted two of the latter type,
MCT-8 and MCT-10, which are ‘particularly active’. ‘The expression of MCT-8
and MCT-10 stimulates the cellular
uptake of T3 and T4’, he said. He also
outlined a recent discovery in respect of
thyroid dysfunction in Allan-HerndonDudley syndrome, a rare disorder that
causes severe mental retardation.
A study by Prof Visser and his team
found MCT-8 mutations in all 17 patients
included in a study they undertook. This
led them to conclude that the syndrome
arises from thyroid hormone resistance,
with the putative mechanism being
impaired T3 uptake by the central nervous system as a result of the mutations in
transporter MCT-8.
Epidemiology and pathophysiology of thyroid dysfunctions
Dr Gregory Hough, a specialist physician/endocrinologist in private practice in
Port Elizabeth, underscored that autoimmune hypothyroidism is more common in
females than in males.
Focusing on Hashimoto’s thyroiditis,
he noted that all the following mechanisms of injury potentially play a role:
molecular mimicry, bystander activation,
thyroid cell expression of HLA antigens
and apoptosis. ‘Thyroid immunity is especially important, as immune tolerance is
lost in autoimmune disease. The targets of
autoimmunity are thyroglobulin, thyroid
peroxidase and TSH receptors.’
In the case of thyroglobulin, the question is not why autoimmunity develops
but how immune tolerance is maintained,
given that thyroglobulin is exposed to
many risk factors, including environmental ones. ‘An increasing number of
pathogenic T-cell determinants are being
discovered’, he said.
With regard to thyroid peroxidase, he
observed that antibodies seem to develop
as a result of antigens presented by thyrocytes and appear to play a more pathogenic role than was previously assumed.
‘TSH receptor antibodies can be either
inhibitory or stimulatory; the former
predominate in Hashimoto’s disease’, he
said.
Turning to the genetics of thyroid
disease, he noted, ‘Recent interest in
chemokines has improved our understanding of their critical role in the initiation and maintenance of the immune
response’.
Autoimmune thyroiditis
Prof John Lazarus of Cardiff University
School of Medicine, Wales, UK reported
on the aetiology/epidemiology, detection, treatment and control of autoimmune thyroiditis, also focusing mainly on
Hashimoto’s thyroiditis. ‘Environmental
and genetic factors combine to produce
thyroid cell damage, causing an aberrant immune response and a Th1/Th2
imbalance. We’re also recognising the
importance of a new player, Th17, in
Hashimoto’s disease, and there is much
to be discovered about this phenotype and
its actions.’
Prof Lazarus underscored that the
immunology of autoimmune thyroiditis
is very complex and that while the basic
mechanisms are understood, much of the
detail is not.
Environmental factors play a role
in the activation of the autoimmune
5
response. These include smoking, stress,
drugs (notably lithium, amiodarone and
interferon-alpha), irradiation, selenium/
magnesium intake, infections, allergies
and being pregnant/postpartum.
‘TPO antibodies are an important
marker of autoimmune thyroiditis and
TPO antibody abnormality leads to
thyroid dysfunction that may be either
overt or subclinical’, said Prof Lazarus.
Hashimoto’s disease affects mainly
women over the age of 50, who can be
either euthyroid or hypothyroid. It is associated with the presence of goitre, TPO
antibodies with or without TgAB, hypoechogenicity, as well as the presence of
other autoimmune diseases, notably rheumatoid arthritis, but also coeliac disease,
Addison’s disease, pernicious anaemia,
vitiligo and type 1 diabetes.
‘Thyroid failure is common in adults,
especially women’, continued Prof
Lazarus, ‘and it often goes unrecognised
due to its protean and often non-specific
symptomatology. The incidence increases
with age and is associated with raised
levels of both total and LDL cholesterol. All hyperlipidaemic patients should
therefore undergo thyroid function tests
to ascertain whether they might not also
have subclinical hypothyroidism.
‘Subclinical hypothyroidism is associated with a higher prevalence of both
myocardial infarction and aortic atherosclerosis in elderly women, and it’s been
shown to be as significant as other more
well-known risk factors.’ Hypothyroidism
is also characterised by psychiatric associations and there is a great deal of overlap between the condition and depression.
The doctor’s clinical index of suspicion
should therefore be high.
There is currently some controversy
around screening for hypothyroidism in
pregnancy. Guidelines advise that it be
undertaken when there is a history of
thyroid disease, goitre, suggestive symptoms, a family history of thyroid disease,
type 1 diabetes and if the patient has
undergone head/neck irradiation.
Levothyroxine is the treatment
of choice. ‘It is commonly prescribed
and reliable’, observed Prof Lazarus.
‘However, it has a very narrow therapeutic/toxic range that can have significant
clinical consequences, including cardiovascular morbidity and mortality (when
taken in excess) and raised LDL cholesterol levels and fatigue (when there is
underdosing).
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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 2, March/April 2010
Looking to the future, Prof Lazarus
foresees a further dissection of the immune
response as well as more insight into the
long-term pathogenetic significance of
antibodies. ‘More auto-antigens might
still be discovered and we will learn more
about genetic predisposition and environmental factors.’ He also anticipates the
development of immune ‘designer drugs’.
‘But for now… T4 rules, OK?’
Cardiovascular manifestations in
hypothyroidism
From a clinical perspective, there are only
three variations in the status of the thyroid
– normal (in which case it requires no
treatment), abnormal (where treatment is
essential) and where subclinical disease
is present. The latter area is where there is
still lack of clarity and some controversy.
‘Is subclinical hypothyroidism important to the clinician?’ asked Prof James
Ker (jun) of the University of Pretoria.
Subclinical hypothyroidism affects five to
15% of the general population, is defined
as an increased serum TSH level with
normal free T4 levels and may be associated with increased morbidity from cardiovascular disease. Whether it should be
viewed as a risk factor on a par with blood
pressure and raised cholesterol remains
controversial, however.
‘Some, but not all, studies have shown
a clear association between subclinical hypothyroidism and ischaemic heart
disease’, continued Prof Ker. ‘There may
be an age influence in that the incidence of IHD is higher in those under 65
years of age. Subclinical hypothyroidism
might therefore be a more important risk
factor in the young and may even be
cardiovascular-protective in the elderly.’ A
reduced mortality risk has been observed
in patients over the age of 85 with mild
hypothyroidism.14
Overt hypothyroidism, on the other
hand, is clearly associated with increased
risk of atherosclerosis, increased CRP
levels, endothelial dysfunction, increased
arterial stiffness and altered coagulation parameters. All these measures have
been shown to regress with levothyroxine administration. ‘The cardiovascular
benefits of replacement therapy in overt
hypothyroidism are therefore unquestionable’, said Prof Ker.
A broad meta-analysis of diverse patient
groups, including African-American
patients, published in the International
Journal of Cardiology in 200815 showed a
clear and significant association between
subclinical hypothyroidism and coronary
heart disease at baseline. While subclinical hypothyroidism did not increase allcause mortality, there was a significantly
higher incidence of cardiovascular mortality at follow up.
Prof Ker observed that a single measurement of low serum TSH in individuals
60 years and older has been shown to
be associated with increased mortality
from all causes, particularly cardiovascular disease.15 ‘This suggests that subclinical hyper- and hypothyroidism might be
equally bad for the heart.’
Because subclinical hypothyroidism
is the result of a mix of aetiologies, treatment requires individualisation, especially in autoimmune contexts. A potential
pathophysiological mechanism involves
the autoimmunity often found in subclinical hypothyroidism.
The autoimmunity may cause local
inflammation that induces coronary
atherosclerosis – meaning that a single
autoimmune process affects both the heart
and thyroid. Other mechanisms include
an atherogenic lipid profile induced by
subclinical hypothyroidism. Thyroid
hormones have also been shown to inhibit
collagen-induced platelet aggregation in
vitro. ‘Platelet activity is a major culprit
in IHD’, said Prof Ker. ‘The increased
peripheral vascular resistance seen with
subclinical hypothyroidism can also result
in hypertension.’
When it comes to the relationship
between subclinical hypothyroidism and
type 2 diabetes, Prof Ker cited a 2007
study published in Diabetic Medicine
that examined the relationship between
subclinical hypothyroidism and the prevalence of retinopathy, nephropathy, cardiovascular disease and mortality in type 2
diabetics not taking thyroid replacement
therapy.2 ‘The prevalence in these patients
is high (in another study up to 17%).
The study found a higher frequency
of both nephropathy and cardiovascular events in those patients who had
subclinical hypothyroidism, although the
latter finding was non-significant after
adjustment for microalbuminuria. It was
the first report to show that subclinical
hypothyroidism may be an independent
risk factor for nephropathy, although not
retinopathy in type 2 diabetics,’ he said.
Brachial-ankle pulse-wave velocity is
a parameter of arterial stiffening and
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an independent predictor of cardiovascular events. Treating subclinical hypothyroidism with levothyroxine improves this
parameter. This is likewise the case with
impaired coronary flow and microvascular function.
Plasma viscosity, a cardiovascular risk
factor, is also associated with subclinical
hypothyroidism, and is usually accompanied by low HDL cholesterol levels
in this context. Once again, patient
profiles improve with thyroid treatment.
‘Levothyroxine is therefore beneficial in
restoring cardiac function abnormalities
in the presence of subclinical hypothyroidism and has even shown benefit in
patients with euthyroid autoimmune
thyroiditis’, said Prof Ker.
Key conclusions
•• Subclinical hypothyroidism is clearly
associated with an increase in coronary heart disease, especially in those
under 65 years old.
•• It is accompanied by myocardial functional abnormalities, both systolic and
diastolic, and these are evident even in
euthyroid active thyroiditis.
•• It has negative effects on coronary
flow reserve and microvascular function, pulse-wave velocity and plasma
viscosity.
•• It raises the risk for nephropathy in
type 2 diabetes.
Looking to the future, he speculated that
in time, the upper limit of normal for TSH
might be lowered to 3, or even 2.5.
Subclinical hypothyroidism –
where do we stand today?
Prof Said Khader of the Dr Suliaman Al
Habib Centre in Riyadh, Saudi Arabia
takes issue with the term ‘subclinical
hypothyroidism’, preferring instead to
call the condition ‘mild thyroid failure’
(MTF). He contends that there are almost
always some symptoms associated with it,
even though they may be mild enough not
be noticed by patients.
‘It’s a very scary condition’, he said,
‘and many patients have no obvious risk
factors. Its clinical features are diverse
and potentially affect virtually every part
of the body. We know that cholesterol
levels increase with rising TSH. This
may explain the risk for coronary heart
disease, which is more common in those
with MTF than it is in diabetics. MTF
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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 2, March/April 2010
and depression are both common, and the
overlap in symptoms often makes it difficult to differentiate between the two.’
Prof Khader defines MTF as an isolated elevated TSH level in the setting of
normal T3 and T4 levels. Symptoms may
be present or absent and various professional bodies differ when it comes to
screening recommendations. Likewise,
the TSH reference range for normal has
been the focus of considerable debate,
as this level is critical for diagnosing
subclinical thyroid dysfunction. Like Prof
Ker, he is of the opinion that the optimal
level will be lowered in the future.
‘The worldwide prevalence of MTF is
one to 10%, and women over 60 are most
affected. The risks include progression
to overt thyroid disease, dyslipidaemia,
cardiac dysfunction and atherosclerosis,
neuropsychiatric symptoms, infertility and miscarriage risk and impaired
foetal development. Consequently, many
patients report symptoms that are easily
confused with those of other conditions.’
The potential vascular complications include: elevated total cholesterol
and LDL cholesterol levels, increased
peripheral vascular resistance, alteration
in endothelium-mediated vasodilation,
increased C-reactive protein levels, and
hypertension. Cardiac effects include
corrected QT intervals that are significantly prolonged, and impaired ventricular systolic and diastolic function. MTF
has also been identified as a potential
cause of aortic atherosclerosis in women.
Prof Khader cited the findings of
Canaris et al.17 that the treatment of MTF
may aid in the treatment of hyperlipidaemia and prevent associated cardiovascular
morbidity. ‘Quality of life is important’,
he said, ‘and treatment with levothyroxine
can help patients to feel better’.
Levothyroxine therapy can prevent
progression to overt hypothyroidism,
improve serum lipid profiles thus reducing cardiovascular risk, as well as address
psychiatric symptoms. ‘At the same time
it’s important to bear in mind factors
that may reduce its effectiveness, such
as malabsorption syndromes, intake of
substances that reduce absorption (e.g.
ferrous sulphate, espresso coffee) and
concomitant use of drugs that reduce
clearance, such as rifampicin and
carbamazepine.’
Concluding, Prof Khader made the
following points:
•• Individuals with TSH levels between 5
and 10 should be treated selectively.
•• Levothyroxine replacement therapy
should be reserved for patients with
goitre, women who are pregnant or
planning to fall pregnant, and patients
with depression or bipolar disorder.
•• Patient preference, clinical circumstances, age, symptoms, presence of
thyroid antibodies and progression of
TSH over time should all be taken into
account.
•• Mayo clinic data show that individuals
with TSH > 8 have a high likelihood
of progressing to overt hypothyroidism
in four years, so treatment is recommended.
Pitfalls in treatment with
levothyroxine
The number of pitfalls associated with
levothyroxine therapy is significant, so
patients need to consult qualified physicians. This is according to Prof Peter
Laurberg of Aarhus University Hospital,
Denmark.
Levothyroxine is contraindicated
where there is known intolerance to the
drug, and in patients who have untreated
thyrotoxicosis, Addison’s disease, acute
myocardial infarction, acute myocarditis,
acute pancreatitis or untreated pulmonary insufficiency/adrenal insufficiency.
‘Also, watch out for low blood pressure,
a pattern of low sodium/high potassium
levels and don’t simply administer in
the presence of low T4 levels without
appropriate TSH evaluation, as one needs
to consider secondary hypothyroidism’,
he said.
There are also pharmacy pitfalls. Prof
Laurberg cited an instance of a formulation processed by pharmacists in Brazil
where patients ended up taking 10 times
the normal dose. He underscored that
patients and doctors need to be informed
when reformulations enter the market.
Not doing so is irresponsible and qualifies as patient neglect.
‘The introduction of a reformulation
of levothyroxine in New Zealand led to
a 2 000-fold increase in reported adverse
events. Something similar happened in
Denmark. The possible cause is that a
change in bioavailability led to an abnormal thyroid state, but because no-one had
been told, no-one had checked.’
Overtreatment can have significant
consequences. Prof Laurberg cited a 2002
study by Cooper and Ridgway to the
7
effect that iatrogenic hyperthyroidism as a
result of insufficiently controlled levothyroxine therapy causes up to 17 000 cases
of atrial fibrillation in the USA each year.
‘The most common pitfall here is lack of
control in dosing and adjustment. Doctors
also make the mistake of believing that all
patients are similar and that “normal” is
always the same.’
Prof Laurberg maintains that there is
ample room to adjust the dose within the
reference range if patients are complaining. A pitfall to avoid here is evaluating
the effect of this after only a week. ‘You
need to allow four to six weeks until a
new steady-state concentration has been
reached’, he said.
Physicians need to bear in mind that
when the thyroid state is changed, other
parameters are potentially changed
too. For example, when levothyroxine
therapy is withdrawn from patients also
taking lipid-lowering agents, their risk of
myopathy increases. Levothyroxine can
also interact with anticoagulants such as
warfarin, to the detriment of the patient.
‘We should be warning young women
on levothyroxine that they need to be
carefully controlled during pregnancy. Because pregnancy increases their
levothyroxine requirement, the dose must
be adjusted accordingly’, he stated.
Prof Laurberg summarised the pitfalls
as follows:
•• Look for adrenal insufficiency and
heart disease before introducing therapy.
•• TSH is not a valid measure of function
in secondary hypothyroidism.
•• Bioactivity depends on the preparation.
•• Patients’ normal range is narrower than
that in laboratory reference tests.
•• Remember increased needs in pregnancy.
•• Control needs to be checked regularly.
•• In instances where findings are anomalous, consider whether the problem
may not lie with the thyroid function
tests being used and do additional testing using an alternative method.
•• Absorption is partial only, and depends
on many variable factors, including
food, medicine and vitamin intake.
Report compiled by J Aalbers, Special
Assignments Editor, and Peter Wagenaar, Gauteng
correspondent.
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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 2, March/April 2010
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The legacy effect …
proven by
1998
1977
Metformin (Glucophage®)
is established as the
foundation of Type 2
Diabetes treatment 1
Start of UKPDS
2008
2006
Metformin therapy should
be initiated concurrently
with lifestyle intervention
at diagnosis 2
Early lowering of glucose with a
sulphonylurea*-insulin or metformin†
had protective effects against
diabetic complications in patients
with Type 2 Diabetes, even 10 years
after randomisation ended 3
†
Glucophage® the sole metformin used in UKPDS * Sulphonylurea therapy included glibenclamide
References: 1. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood glucose control with metformin on complications in overweight patients with Type 2 Diabetes (UKPDS 34). Lancet 1998;352:854-65. 2. Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycaemia in
Type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologica 2006;49(8):1711-1721. 3. Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up
of intensive glucose control in Type 2 Diabetes. N Engl J Med 2008;359:1-3.
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